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新型 ROCK2 选择性抑制剂 NRL-1049 可保护急性损伤后的血脑屏障。

The novel ROCK2 selective inhibitor NRL-1049 preserves the blood-brain barrier after acute injury.

机构信息

Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Department of Biomedical Engineering and Physics, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands.

出版信息

J Cereb Blood Flow Metab. 2024 Nov;44(11):1238-1252. doi: 10.1177/0271678X241238845. Epub 2024 Jun 4.

DOI:10.1177/0271678X241238845
PMID:38833563
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11542141/
Abstract

Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury.

摘要

内皮血脑屏障 (BBB) 功能障碍是脑损伤病理生理学的关键。Rho 相关蛋白激酶 (ROCK) 的激活会破坏损伤大脑中的 BBB 完整性。我们旨在测试一种新型 ROCK2 抑制剂在急性脑损伤后维持 BBB 的疗效。我们对一种新型选择性 ROCK2 抑制剂 NRL-1049 及其第一个代谢产物 1-羟基-NRL-1049（此处称为 NRL-2017）的分子结构、药效学和药代动力学特性进行了表征，并测试了 NRL-1049 在急性脑损伤啮齿动物模型中对 BBB 完整性的疗效。我们的数据表明，NRL-1049 和 NRL-2017 均可抑制 ROCK 活性，对 ROCK2 的选择性分别是 ROCK1 的 44 倍和 17 倍。在皮层冷冻损伤的小鼠模型中进行测试时，NRL-1049 显著减轻了水含量的增加。有趣的是，在冷冻损伤后 2 小时内，载体组中有 60%的小鼠发生癫痫发作，而 NRL-1049 组中无一例发生。在自发性高血压大鼠中，与载体组相比，NRL-1049 可减轻短暂性大脑中动脉闭塞后伊文思蓝外渗的急剧增加。出血性转化也减少。我们表明，选择性 ROCK2 抑制剂 NRL-1049 是一种有前途的候选药物，可在脑损伤后维持 BBB。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/55ba9598eae7/10.1177_0271678X241238845-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/a3bae32c085a/10.1177_0271678X241238845-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/173b517eb23d/10.1177_0271678X241238845-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/8a2daa3bdfc0/10.1177_0271678X241238845-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/231bb006c841/10.1177_0271678X241238845-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/55ba9598eae7/10.1177_0271678X241238845-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/a3bae32c085a/10.1177_0271678X241238845-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/173b517eb23d/10.1177_0271678X241238845-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/8a2daa3bdfc0/10.1177_0271678X241238845-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/231bb006c841/10.1177_0271678X241238845-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7096/11542141/55ba9598eae7/10.1177_0271678X241238845-fig5.jpg

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